This invention relates generally to novel 1,1-disubstituted cyclic matrix metalloproteases and TNF-xcex1 inhibitors and pharmaceutical compositions containing the same and methods of using the same.
There is now a body of evidence that metalloproteases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMPs (tissue inhibitors of metalloprotease), which form inactive complexes with the MP""s.
Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 52A, 1970, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteases. The available evidence supports that it is the metalloproteases that are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner et al. Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). In addition, aggrecanase has been identified as providing the specific cleavage product of proteoglycan found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22).
Therefore, metalloproteases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 25, 175-184, AP, San Diego, 1990).
Tumor necrosis factor (TNF) is a cell-associated cytokine that is processed from a 26 kd precursor form to a 17 kd active form. TNF has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF with specific antibodies can be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105) and non-insulin dependent diabetes melitus. (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22) and Crohn""s disease (MacDonald T. et al. Clin. Exp. Immunol. 81, 1990, 301).
Compounds which inhibit the production of TNF are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that a matrix metalloprotease or family of metalloproteases, hereafter known as TNF-convertases (TNF-C), as well as other MP""s are capable of cleaving TNF from its inactive to active form (Gearing et al Nature, 1994, 370, 555). This invention describes molecules that inhibit this conversion and hence the secretion of active TNF-xcex1 from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, malaria, Crohn""s disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, OA, RA, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV and non-insulin dependent diabetes melitus.
Since excessive TNF production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may also have a particular advantage in diseases where both mechanisms are involved.
EP 0,780,286 describes MMP inhibitors of formula A: 
wherein Y can be NHOH, R1 and R2 can combine to form a cycloalkyl or heterocycloalkyl group, R3 and R4 can be a variety of groups including H, and R5 can be substituted aryl. Such compounds are not considered to be part of the present invention.
WO 97/20824 depicts MMP inhibitors of formula B: 
wherein ring V contains six atoms, Z is O or S, and Ar is an aryl or heteroaryl group. Ar is preferably a monocyclic aryl group with an optional para substituent or an unsubstituted monocyclic heteroaryl group. Compounds of this sort are not considered to be part of the present invention.
EP 0,818,442 illustrates MMP inhibitors of formula C: 
wherein Ar is optionally substituted phenyl or naphthyl, Z can be absent and X and Y can be a variety of substituents. Compounds like this are not considered to be part of the present invention.
WO 98/39316 presents MMP inhibitors of formula D: 
wherein R6 and R7 can combine to form a heterocycle and R1 can be a substituted aryl group. These types of compounds are not considered to be part of the present invention.
WO 97/32846 describes MMP inhibitors of formula E: 
wherein R1 can be a sulfonyl aryl group. Compounds of this sort are not considered to be part of the present invention.
The compounds of the present invention act as inhibitors of MPs, in particular aggrecanase and TNF-xcex1. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibition of aggrecanase, TNF-C, and other metalloproteases by molecules of the present invention indicates they are anti-inflammatory and should prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of OA and RA.
Accordingly, one object of the present invention is to provide novel cyclic hydroxamic acids useful as metalloprotease inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating inflammatory disorders, comprising: administering to a host, in need of such treatment, a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors""discovery that compounds of formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, p1, R1a, R1b, R2, R2a, R2b R3, Ua, Xa, Ya, Z, and Za are defined below, are effective metalloprotease inhibitors.
[1] Thus, in an embodiment, the present invention provides a novel compound of formula I: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from xe2x80x94COR5, xe2x80x94CO2H, CH2CO2H, xe2x80x94CO2R6, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94N(OH)CHO, xe2x80x94N(OH)COR5, xe2x80x94SH, xe2x80x94CH2SH, xe2x80x94SONHRa, xe2x80x94SN2H2Ra, xe2x80x94PO(OH)2, and xe2x80x94PO(OH)NHRa;
ring B is a 3-10 membered carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-1 carbonyl groups, 0-1 double bonds, and from 0-2 ring heteroatoms selected from O, N, NR2, and S(O)p, provided that ring B contains other than a Sxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94O bond and provided that N-R2 forms other than an Nxe2x80x94O, Nxe2x80x94N, or Nxe2x80x94S bond;
Z is absent or selected from a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rb;
Ua is absent or is selected from: O, NRa1, C(O), C(O)O, OC(O), C(O)NRa1, NRa1C(O), OC(O)O, OC(O)NRa1, NRa1C(O)O, NRa1C(O)NRa1, S(O)p, S(O)pNRa1, NRa1S(O)p, and NRa1SO2NRa1;
Xa is absent or selected from C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
Ya is absent or selected from O, NRa1, S(O)p, and C(O);
Za is selected from a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R1a is selected from H, C1-4 alkyl, phenyl, benzyl, CH2OR3, and CH2NRaRa1;
R1b is selected from H, C1-4 alkyl, phenyl, benzyl, CH2OR3, and CH2NRaRa1;
alternatively, R1a and R1b combine to form a 3-6 membered ring consisting of: carbon atoms and 0-1 heteroatoms selected from O, S, S(O), S(O)2, and NRa;
provided that when R1a and R1b are hydrogen and ring B is a heterocycle, then Za is the following: 
ring C is phenyl or pyridyl and is substituted with 0-2 Rc;
ring D is selected from phenyl, pyridyl, pyridazinyl, pyrimidyl, and pyrazinyl, and is substituted with 0-3 Rc;
R2 is selected from Q, C1-10 alkylene-Q substituted with 0-3 Rb1, C2-10 alkenylene-Q substituted with 0-3 Rb1, C2-10 alkynylene-Q substituted with 0-3 Rb1, (CRaRa1)r1O(CRaRa1)r-Q, (CRaRa1)r1NRa(CRaRa1)r-Q, (CRaRa1)r1C(O)(CRaRa1)r-Q, (CRaRa1)r1C(O)O(CRaRa1)r-Q, (CRaRa1)r1OC(O)(CRaRa1)r-Q, (CRaRa1)r1C(O)NRaRa1, (CRaRa1)r1C(O)NRa(CRaRa1)r-Q, (CRaRa1)r1NRaC(O)(CRaRa1)r-Q, (CRaRa1)r1OC(O)O(CRaRa1)r-Q, (CRaRa1)r1OC(O)NRa(CRaRa1)r-Q, (CRaRa1)r1NRaC(O)O(CRaRa1)r-Q, (CRaRa1)r1NRaC(O)NRa(CRaRa1)r-Q, (CRaRa1)r1S(O )p(CRaRa1)r-Q, (CRaRa1)r1SO2NRa(CRaRa1)r-Q (CRaRa1)r1NRaSO2(CRaRa1)r-Q, and (CRaRa1)r1NRaSO2NRa(CRaRa1)r-Q;
R2a is selected from H, C1-4 alkyl, phenyl, benzyl, CH2OR3, and CH2NRaRa1;
R2b is selected from H, C1-4 alkyl, phenyl, benzyl, CH2OR3, and CH2NRaRa1;
alternatively, R2a and R2b combine to form a 3-6 membered ring consisting of: carbon atoms and 0-1 heteroatoms selected from O, S, S(O), S(O)2, and NRa;
Q is selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rd and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rd;
R3, at each occurrence, is selected from Q1, C1-6 alkylene-Q1, C2-6 alkenylene-Q1 C2-6 alkynylene-Q1, (CRaRa1)r1O (CH2)r-Q1, (CRaRa1)r1NRa(CRaRa1)r-Q1, (CRaRa1)r1NRaC(O)(CRaRa1)r-Q1, (CRaRa1)r1C(O)NRa(CRaRa1)r-Q1, (CRaRa1)r1C(O)(CRaRa1)r-Q1, (CRaRa1)r1C(O)O(CRaRa1)r-Q1, (CRaRa12)r1S(O)p(CRaRa1)r-Q1, and (CRaRa1)r1SO2NRa(CRaRa1)r-Q1;
alternatively, when two R3""s are attached to the same carbon atom, they combine to form a 3-8 membered carbocyclic or heterocyclic ring consisting of: carbon atoms and 0-3 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rd;
Q1 is selected from H, phenyl substituted with 0-3 Rd, naphthyl substituted with 0-3 Rd and a 5-10 membered heteroaryl consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rd;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Ra1, at each occurrence, is independently selected from H and C1-4 alkyl;
alternatively, Ra and Ra1 when attached to a nitrogen are taken together with the nitrogen to which they are attached to form a 5 or 6 membered ring comprising carbon atoms and from 0-1 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)O, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, and CF2CF3;
Rb1, at each occurrence, is independently selected from ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, and NRaRa1;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)O, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, CF2CF3, C3-10 carbocyclic residue and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)O, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, CF2CF3, C3-10 carbocyclic residue and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
R5, at each occurrence, is selected from C1-10 alkyl substituted with 0-2 Rb, and C1-8 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
R6, at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(Ra)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-10 alkyl-NR7R7a, xe2x80x94CH(R8)OC(xe2x95x90O)R9, and xe2x80x94CH(R8)OC(xe2x95x90O)OR9;
R7 is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R7a is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-8 alkyl substituted with 1-2 Rf, C3-8 cycloalkyl substituted with 1-2 Rf, and phenyl substituted with 0-2 Rb;
Rf, at each occurrence, is selected from C1-4 alkyl, C3-8 cycloalkyl, C1-5 alkoxy, and phenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
p1 is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
r1, at each occurrence, is selected from 0, 1, 2, 3, and 4.
[2] In a preferred embodiment, the present invention provides a novel compound of formula II: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94N(OH)CHO, xe2x80x94N(OH)COR5, xe2x80x94SH, and xe2x80x94CH2SH;
ring B is a 4-7 membered carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-1 carbonyl groups, 0-1 double bonds, and from 0-2 ring heteroatoms selected from O, N, and NR2, provided that ring B contains other than an Oxe2x80x94O bond and provided that Nxe2x80x94R2 forms other than an Nxe2x80x94O, Nxe2x80x94N, or Nxe2x80x94S bond;
Z is absent or selected from a C3-6 carbocyclic residue substituted with 0-4 Rb and a 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)pand substituted with 0-3 Rb;
Ua is absent or is selected from: O, NRa1, C(O), C(O)O, C(O)NRa1, NRa1C(O), S(O)p, and S(O)pNRa1;
Xa is absent or selected from C1-4 alkylene and C2-4 alkynylene;
Ya is absent or selected from O and NRa1;
Za is selected from H, a C3-10 carbocyclic residue substituted with 0-5 Rc and a 5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R2 is selected from Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, (CRaRa1)r1O(CRaRa1)r-Q, (CRaRa1)r1NRa(CRaRa1)r-Q, (CRaRa1)r1C(O)(CRaRa1)r-Q, (CRaRa1)r1C(O)O(CRaRa1)r-Q, (CRaRa1)rC(O)NRaRa1, (CRaRa1)r1C(O)NRa(CRaRa1)r-Q, (CRaRa1)r1S(O)p(CRaRa1)r-Q, and (CRaRa1)r1SO2NRa(CRaRa1)r-Q;
Q is selected from H, a C3-6 carbocyclic residue substituted with 0-5 Rd, and a 5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rd;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Ra1, at each occurrence, is independently selected from H and C1-4 alkyl;
alternatively, Ra and Ra1 when attached to a nitrogen are taken together with the nitrogen to which they are attached to form a 5 or 6 membered ring comprising carbon atoms and from 0-1 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3, C3-6 carbocyclic residue and a 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3, C3-6 carbocyclic residue and a 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
R5, at each occurrence, is selected from C1-6 alkyl substituted with 0-2 Rb, and C1-4 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
R6, at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(Ra)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-10 alkyl-NR7R7a, xe2x80x94CH(R8)OC(xe2x95x90O)R9, and xe2x80x94CH(R8)OC(xe2x95x90O)OR9;
R7 is selected from H and C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R7a is selected from H and C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-6 alkyl substituted with 1-2 Rf, C3-6 cycloalkyl substituted with 1-2 Rf, and phenyl substituted with 0-2 Rb;
Rf, at each occurrence, is selected from C1-4 alkyl, C3-6 cycloalkyl, C1-5 alkoxy, and phenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
r1, at each occurrence, is selected from 0, 1, 2, 3, and 4.
[3] In a more preferred embodiment, the present invention provides a novel compound of formula III: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94N(OH)CHO, and xe2x80x94N(OH)COR5;
B1 is selected from NR2, O, and CHR2, provided that Nxe2x80x94R2 forms other than an Nxe2x80x94O, Nxe2x80x94N, or Nxe2x80x94S bond;
Z is absent or selected from a C5-6 carbocyclic residue substituted with 0-3 Rb and a 5-6 membered heteroaryl comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rb;
Ua is absent or is selected from: O, NRa1, C(O), C(O)NRa1, S(O)p, and S(O)pNRa1;
Xa is absent or selected from C1-2 alkylene and C2-4 alkynylene;
Ya is absent or selected from O and NRa1;
Za is selected from H, a C5-6 carbocyclic residue substituted with 0-3 Rc and a 5-10 membered heteroaryl comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)por S(O)pxe2x80x94S(O)p group;
R2 is selected from Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, (CRaRa1)r1O(CRaRa1)r-Q, (CRaRa1)r1NRa(CRaRa1)r-Q, (CRaRa1)r1C(O)(CRaRa1)r-Q, (CRaRa1)r1C(O)O(CRaRa1)r-Q, (CRaRa2 )r1C(O)NRaRa1, (CRaRa2)r1C(O)NRa(CRaRa1)r-Q, and (CRaRa1)r1S(O)p(CRaRa1)r-Q;
Q is selected from H, a C3-6 carbocyclic residue substituted with 0-3 Rd and a 5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rd;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Ra1 at each occurrence, is independently selected from H and C1-4 alkyl;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
Rb, at each occurrence, is independently selected from C1-4 alkyl, ORa, Cl, F, xe2x95x90O, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3 and phenyl;
R5, at each occurrence, is selected from C1-4 alkyl substituted with 0-2 Rb, and C1-4 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4;
r1, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
s and s1 combine to total 1, 2, 3, or 4.
[4] In an even more preferred embodiment, the present invention provides a novel compound of formula IV: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
Z is absent or selected from phenyl substituted with 0-3 Rb and pyridyl substituted with 0-3 Rb;
Ua is absent or is O;
Xa is absent or is selected from CH2, CH2CH2, and C2-4 alkynylene;
Ya is absent or is O;
Za is selected from H, phenyl substituted with 0-3 Rc, pyridyl substituted with 0-3 Rc, and quinolinyl substituted with 0-3 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, or Oxe2x80x94O group;
R2 is selected from Q, C1-6 alkylene-Q, C2-6 alkynylene-Q, (CRaRa1)r1O(CRaRa1)r-Q, (CRaRa1)r1NRa(CRaRa1)r-Q, C(O)(CRaRa1)r-Q, C(O)O(CRaRa1)r-Q, C(O)NRa(CRaRa1)r-Q, and S(O)p(CRaRa1)r-Q;
Q is selected from H, cyclopropyl substituted with 0-1 Rd, cyclobutyl substituted with 0-1 Rd, cyclopentyl substituted with 0-1 Rd, cyclohexyl substituted with 0-1 Rd, phenyl substituted with 0-2 Rd and a heteroaryl substituted with 0-3 Rd, wherein the heteroaryl is selected from pyridyl, quinolinyl, thiazolyl, furanyl, imidazolyl, and isoxazolyl;
Ra, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Ra1, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Ra2, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Rb, at each occurrence, is independently selected from C1-4 alkyl, ORa, Cl, F, xe2x95x90O, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3 and phenyl;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, and 3;
r1, at each occurrence, is selected from 0, 1, 2, and 3; and,
s and s1 combine to total 2, 3, or 4.
[5] In another preferred embodiment, the present invention provides a novel compound selected from the group:
N-hydroxy-2-{2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-2-pyrrolidinyl}acetamide;
N-hydroxy-2-{1-methyl-2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-2-pyrrolidinyl}acetamide;
N-hydroxy-2-{1-isobutyl-2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-2-pyrrolidinyl}acetamide;
N-hydroxy-2-[2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-1-(3-pyridinyl)-2-pyrrolidinyl}acetamide;
2-{1-acetyl-2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-2-pyrrolidinyl}-N-hydroxyacetamide;
N-hydroxy-2-{3-[({4-{(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-pyrrolidinyl}acetamide;
N-hydroxy-2-{1-methyl-3-[({4-{(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-pyrrolidinyl}-acetamide;
N-hydroxy-2-{1-isopropyl-3-[({4-{(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-pyrrolidinyl}acetamide;
N-hydroxy-2-{1-isobutyl-3-[({4-{(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-pyrrolidinyl}acetamide;
N-hydroxy-2-{3-[({4-{(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-1-neopentyl-3-pyrrolidinyl}acetamide;
N-hydroxy-2-{2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-2-piperidinyl}acetamide;
N-hydroxy-2-{1-methyl-2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-2-piperidinyl}acetamide;
N-hydroxy-2-{1-isobutyl-2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-2-piperidinyl}acetamide;
N-hydroxy-2-{3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfinyl)methyl]-3-piperidinyl}acetamide;
N-hydroxy-2-{1-methyl-3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfinyl)methyl]-3-piperidinyl}acetamide;
N-hydroxy-2-{1-isopropyl-3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfinyl)methyl]-3-piperidinyl}acetamide;
N-hydroxy-2-{3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-piperidinyl}acetamide;
N-hydroxy-2-{1-methyl-3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-piperidinyl}acetamide;
N-hydroxy-2-{1-isopropyl-3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-piperidinyl}acetamide;
N-hydroxy-2-{1-isobutyl-3-[({4-[(2-methyl-4-quinolinyl)methoxylphenyl}sulfonyl)methyl]-3-piperidinyl}acetamide;
N-hydroxy-2-{4-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-4-piperidinyl}acetamide;
N-hydroxy-2-{1-methyl-4-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-4-piperidinyl}acetamide;
N-hydroxy-2-{2-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]tetrahydro-2-furanyl}acetamide;
N-hydroxy-2-{1-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]cyclobutyl}acetamide;
N-hydroxy-2-{1-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfinyl)methyl]cyclobutyl}acetamide;
N-hydroxy-2-{1-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfanyl)methyl]cyclobutyl}acetamide;
N-hydroxy-2-{1-[({4-[(2-methyl-4-quinolinyl) methoxy]phenyl}sulfonyl)methyl]cyclohexyl}acetamide;
N-hydroxy-2-{1-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfanyl)methyl]cyclohexyl}acetamide;
N-hydroxy-2-{3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-oxetanyl}acetamide;
N-hydroxy-2-{1-methyl-3-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-2-oxopyrrolidinyl}acetamide;
N-hydroxy-2-{1-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]cyclopentyl}acetamide;
N-hydroxy-2-[5-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-(3-pyridinyl)-4,5-dihydro-5-isoxazolyl]acetamide;
N-hydroxy-2-[5-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-(4-pyridinyl)-4,5-dihydro-5-isoxazolyl]acetamide; and,
N-hydroxy-2-{4-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]tetrahydro-2H-pyran-4-yl}acetamide;
or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating an inflammatory disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat an inflammatory disorder.
In another embodiment, the present invention provides a novel method of treating a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating, wherein the disease or condition is referred to as acute infection, acute phase response, age related macular degeneration, alcoholism, allergy, allergic asthma, aneurism, anorexia, aortic aneurism, asthma, athersclerosis, atopic dermatitis, autoimmune disease, autoimmune hepatitis, Bechet""s disease, cachexia, calcium pyrophosphate dihydrate deposition disease, cardiovascular effects, chronic fatigue syndrome, chronic obstruction pulmonary disease, coagulation, congestive heart failure, corneal ulceration, Crohn""s disease, enteropathic arthropathy, Felty""s syndrome, fever, fibromyalgia syndrome, fibrotic disease, gingivitis, glucocorticoid withdrawal syndrome, gout, graft versus host disease, hemorrhage, HIV infection, hyperoxic alveolar injury, infectious arthritis, inflammation, intermittent hydrarthrosis, Lyme disease, meningitis, multiple sclerosis, myasthenia gravis, mycobacterial infection, neovascular glaucoma, osteoarthritis, pelvic inflammatory disease, periodontitis, polymyositis/dermatomyositis, post-ischaemic reperfusion injury, post-radiation asthenia, psoriasis, psoriatic arthritis, pulmonary emphysema, pydoderma gangrenosum, relapsing polychondritis, Reiter""s syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sepsis syndrome, Still""s disease, shock, Sjogren""s syndrome, skin inflammatory diseases, solid tumor growth and tumor invasion by secondary metastases, spondylitis, stroke, systemic lupus erythematosus, ulcerative colitis, uveitis, vasculitis, and Wegener""s granulomatosis.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional more preferred embodiments. It is also to be understood that each individual element of the preferred embodiments is intended to be taken individually as its own independent preferred embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Geometric isomers of double bonds such as olefins and Cxe2x95x90N double bonds can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., Rb) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-10 alkyl (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl, is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. C2-10 alkenyl (or alkenylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkenyl groups. xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. C2-10 alkynyl (or alkynylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkynyl groups.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic groupxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic groupxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, NH, O and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc . . . ) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
As used herein, xe2x80x9ctreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit a desired metalloprotease in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of the desired target) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased anti-inflammatory effect, or some other beneficial effect of the combination compared with the individual components.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
A variety of compounds of formula (I) wherein A is a hydroxamic acid group can be produced in accordance with generic synthetic schemes 1-3. The hydroxyl group of key intermediate 1 is activated under the conditions known in literature (Scheme 1). One way to activate the hydroxyl group is to convert it to the corresponding halide. In scheme 1, only a few methods to make the corresponding bromide are listed for illustration purposes. But, this invention is not intended to be limited to these listed methods.
Another way to activate the hydroxyl group of compound 1 is to transform it to the corresponding sulfonate. The methanesulfonate, toluenesulfonate, and trifluoromethanesulfonate are included in scheme 1 for illustration purposes. Under suitable conditions, a mercaptan will displace the leaving group x of compound 2 to form product 3. The mercaptan used could be the whole right fragment necessary for formula (I) or just a portion of it. In the latter case, the whole right arm in formula (I) can be assembled later on via alkylation, Pd or Cu mediated coupling, acylation, etc. (see Scheme 4 for more details).
The oxidation of the sulphide can be achieved under a variety of conditions. Depending on what the goal is, either a sulphoxide or sulfone derivative can be made by controlling the stoichiometric ratio of the oxidation reagent to the substrate or by choosing different reagents. Basically, when the sulfone is required, Oxone(copyright) is the first choice if there are basic nitrogens or double bonds in the parent molecule. In order to oxidize sulphides to sulphoxides, sodium periodate is better than other reagents in term of chemoselectivity. There are a few reagents listed in scheme 1, such as MCPBA and TPAP/NaIO4, which can be used to oxidize sulphides. But, this description is not intended to exclude any other reagents, which have a capacity to oxidize sulphides and are known in literature.
The hydroxamic acids can be prepared from their corresponding esters via several routes known in literature. The methyl or ethyl ester of compound 4 is directly converted to hydroxamic acid 5 by treatment with hydroxylamine under basic conditions such as KOH or NaOMe in solvents such as methanol. Alternatively, the t-butyl ester of compound 4 is converted to its carboxylic intermediate under TFA conditions. Coupling with hydroxylamine mediated by peptide coupling reagents such as BOP then affords the desired hydroxamic acid 5. 
Intermediate 3 can also be made from the spirolactone 6 (Scheme 2). Under suitable conditions, opening the lactone by a mercaptan shown in scheme 2 results in the corresponding carboxylic acid 7. The mercaptan could be the whole fragment necessary for formula (I) or just a portion of it. In the latter case, the whole right arm can be assembled later on via alkylation, Pd or Cu mediated coupling, acylation, etc. (see Scheme 4 for more details). The carboxylic acid 7 is easily converted to the corresponding methyl ester 3 through the action of CH2N2, TMSCHN2, or HCl/MeOH. 
There is another attractive route to synthesize intermediate 4, starting from an alcohol 8 (scheme 3). The hydroxyl group of key intermediate 8 can be activated under the conditions known in literature. One way to activate the hydroxyl group is to convert it to the corresponding halide. In scheme 3, only a few methods to make the corresponding bromide are listed for illustration purposes. But, this invention is not intended to be limited to these listed methods. Another way to activate the hydroxyl group of compound 8 is to transform it to the corresponding sulfonate. The methanesulfonate, toluenesulfonate and trifluoromethanesulfonate are included in scheme 3 for illustration purpose.
Under suitable conditions, a mercaptan will displace leaving group x of compound 9 to form compound 10. The mercaptan could be the whole fragment necessary for formula (I) or just a portion of it. In the latter case, the whole right arm can be assembled later on via alkylation, Pd or Cu mediated coupling, acylation, etc. (see Scheme 4 for more details). The oxidation of the sulphide can be achieved under a variety of reaction conditions. Depending on what the goal is, either a sulphoxide or sulfone derivative can be made by controlling the stoichiometric ratio of the oxidation reagent with the substrate or by choosing different reagents. Basically, when the sulfone is required, Oxone(copyright) is the first choice if there are basic nitrogens or double bonds in the parent molecule. In order to oxidize sulphides to sulphoxides, sodium periodate is better than other reagents in term of chemoselectivity. There are a few reagents listed in scheme 3, such as MCPBA and TPAP/NaIO4, which can be used to oxidize sulphides, but this invention does not exclude any other reagents, which have the capacity to oxidize sulphides and are known in literature.
In order to transform the allyl group of compound 11 to a two-carbon ester function, a three-step reaction sequence is executed. The first step is to cleave the carbon-carbon double bond to form the corresponding aldehyde. In scheme 3, two different methods are listed for illustration purposes. One method is ozonolysis. The other is dihydroxylation mediated by OSO4, followed by cleavage of the corresponding vicinal diol mediated by NaIO4. The next step is to oxidize the aldehyde to the corresponding carboxylic acid. It can be achieved under the conditions (NaClO2/NaH2PO4/2-methyl-2-butene) as shown in scheme 3. But, this description is not intended to exclude any other known method, which fits this oxidation regimen.
The last step of the sequence is to convert the acid to the methyl ester 4. The simplest way to do it is shown in scheme 3. Both TMSCHN2 and CH2N2 work well. 
4-Mercaptophenol is one of the reagents that are used to prepare a variety of compounds of formula (I). When compound 2 (Xxe2x95x90Cl, Br, I, OMs, OTs, or OTf) reacts with 4-mercaptophenol under basic conditions such as K2CO3 or NaH, in solvents such as acetone or DMF, a displacement takes place and the corresponding product 12 can be produced (Scheme 4). An alternative way to obtain compound 12 is through lactone intermediate 6. Upon heating the mixture of compound 6 and the anion of 4-mercaptophenol generated through the action of NaH in DMF, opening of the lactone of compound 6 affords the corresponding carboxylic acid, which is further transformed to methyl ester 12 through the action of TMSCHN2. The only difference between compound 12 and 13 is the oxidation stage of sulfur atom.
Compound 13 can be made from intermediate 9. In this case, the allyl group of compound 9 has to be transformed to a two-carbon ester function after the introduction of 4-mercaptophenol. Once 4-mercaptophenol displaces the leaving group x in 9 under basic conditions, the resultant compound is subjected to ozonolysis and the cleavage of the terminal double bond affords the corresponding aldehyde. At the same time, the sulphide is oxidized to sulphoxide in situ. The sulphoxide can be reduced to sulphide or further be oxidized to sulphone. After the aldehyde is oxidized by NaClO2/NaH2PO4/2-methyl-2-butene, the resulting carboxylic acid is converted to methyl ester 13 using TMSCHN2 as a methylation agent.
Intermediates 12 and 13 are converted to a variety of compounds such as 14a-c. If an alkylation is chosen to introduce the missing right arm to compounds 12 or 13, conditions like ArCH2X/K2CO3/DMF are very convenient for this execution. Copper-mediated coupling of 12 (or 13) with aryl boric acid provides the biaryl ether (14b) and palladium-mediated coupling of the trifluoromethanesulfonate derivative of compound 12 (or 13) with aryl boric acid affords the biaryl compound (14c). 
Conversion from compound 14 to hydroxamic acid 15 is rather straightforward (Scheme 5). Compound 14 is directly converted to hydroxamic acid 15 under conditions such as NH2OH/KOH/MeOH if the sulfone function is already present in 14. Otherwise, a two-step sequence is required. This sequence includes an Oxone(copyright) oxidation and hydroxamic acid formation if the oxidation stage of sulfur in 14 has not reached the sulfone stage. 
When a nitrogen is present in ring B of compound 14, a variety of compounds can be prepared by changing the substitution group on that nitrogen. The general strategy of this approach is outlined in scheme 6. After the parent compound 16 is assembled, the Boc protection group in 16 is removed under TFA conditions. A number of reactions can be utilized for preparation of different classes of compounds 18. For example, direct alkylation or reductive amination of compound 17 will introduce an alkyl side chain on the nitrogen (see compound 18). On the other hand, acylation of 17 will provide amide derivatives (see compound 18) and sulfonylation will lead to sulfonamide derivatives (see compound 18). 
More complex scaffolds, other than nitrogen containing heterocycle, can be constructed and may provide favorable biological profiles. A few examples are outlined in scheme 7. If the central ring of compound 19 bears a functional group such as hydroxyl group, protected hydroxyl group, ketone, or ketal moiety at the designated position (see compound 19), this functional group provides a handle for further chemical elaboration. For example, when W in 19 is OH, the hydroxyl group can be oxidized to ketone derivative 20 (Vxe2x95x90O) and the ketone may lead to alkene 20 (Vxe2x95x90CH2, CHR, or CR2). If a cycloaddition reaction such as [3+2] is applied to the alkene substrate 20, a spiro product 22 can be obtained. Ring H in 22 can be a 3-7 membered carbocycle or heterocycle. When ring H is a heterocycle, the number of heteroatoms ranges from 1 to 3 and the heteroatoms include O, N and S.
Another way to form a spiro product from ketone 20 involves a Barbier-type addition to the ketone function, followed by ring formation. Similarly, compound 19 can be processed to an internal carbon-carbon double bond derivative 21. A number of reactions can be applied to substrate 21 and a bicyclic skeleton 23 can be built up based on cycloaddition approaches. The scope of ring H in 23 remains the same as that in 22.
Another derivation from compound 24 is to utilize enolate chemistry that allows a number of different electrophiles to be introduced next to either the ester function or the sulfone function (Scheme 8). Depending on where the electrophile is going to be introduced, different approaches can be pursued to achieve the desired product. For example, when an electrophile is going to be introduced next to the carbonyl group, the xcex1-H of the sulfonyl function may compete with the xcex1-H of the ester in the formation of the enolate (see compound 24). Fortunately, this complication can be easily avoided if a sulphide function is chosen instead of a sulfone function (p1=0 in compound 24). On the other hand, when an electrophile is going to be introduced next to the sulfonyl group in 24, a carboxylic acid should not interfere in the introduction of the electrophile at the xcex1-position of the sulfone. For further chemical elaboration of compound 25, a strategy outlined in Scheme 7 can be pursued as well. 
The synthesis of compound 35 is outlined in scheme 9. The orthoester Claisen rearrangement is the key step to establish a required quaternary carbon center (see compound 30). Cleavage of the carbon-carbon double bond in 30 by ozone, followed by reduction, leads to the intermediate 31. The rest of synthesis is straightforward and compound 35 is obtained in four steps. 
Alternative synthesis of compound 35 commences from an ester 36 (Scheme 10). The strategy is to use allyl group as a surrogate for two-carbon ester side chain. The quaternary carbon center is established by alkylation instead of orthoester Claisen rearrangement. Once an allyl group is introduced to the xcex1-position of the ester for establishment of the quaternary center, the ester group is immediately reduced to the corresponding alcohol using DIBAL reduction. The strategy employed for the introduction of 4-mercaptophenol remains the same as illustrated in Scheme 9. Activation of the alcohol, followed by base-mediated 4-mercaptophenol displacement, affords the corresponding coupling product 38. Alkylation on the phenolic OH with 4-chloromethyl-2-methylquinoline mediated by K2CO3, followed by Oxone(copyright) oxidation, leads to sulfone 39. The terminal carbon-carbon double bond in 39 is transformed to the ester function in three steps to provide compound 35 (see Scheme 10 for details). 
An illustration for preparation of an oxygen-containing heterocycle 44a is provided in Scheme 11a. The chemistry employed remains exactly the same as seen in Scheme 10, but the starting material chosen this time is either a tetrahydrofuran derivative or a tetrahydropyran derivative 40a. 
An illustration for preparation of a carbocycle 44b is provided in Scheme 11b. The allylated compound 41b, obtained from allylation of starting material 40b, followed by DIBAL reduction, is subjected to ozonolysis and the resulting hemiacetal is further oxidized to lactone 42b immediately. Upon heating with NaH, 4-mercaptophenol in DMF, followed by treatment of TMSCHN2 in methanol, lactone 42b is converted to compound 43b. After the quinoline moiety is introduced, Oxone(copyright) oxidation of the resulting material affords the final product 44b. 
The synthesis of 4-membered oxygen-containing heterocycle 50 commences from dimethyl allylmalonate 45. LDA deprotonation, followed by addition of BOMCl, furnishes a quaternary center on the xcex1-position of the carbonyl groups. LAH reduction results in diol 46, which is converted to its mono-toluenesulfonate 47 in one step. The mono-toluenesulfonate 47 is subjected to the action of NaH/THF, under which conditions formation of oxetane 48 is realized. Manipulation of allyl group to ester function in 48 can be achieved without any complication and the benzyl group is removed under Pd/C condition in the atmosphere of hydrogen to provide intermediate 49. Following the chemistry analogous to that described in scheme 10, the final compound 50 can be easily prepared from intermediate 49 in four steps. 
Lactam-based compound 54 can be made using chemistry similar to that described in scheme 10. LDA promoted alkylation allows the introduction of an allyl group at the xcex1-position of the lactam function in 51 (see scheme 13). Aldol condensation with paraformaldehyde mediated by LDA furnishes the desired quaternary carbon center in 53. By employing the chemistry analogous to that described in scheme 10, the final compound 54 can be produced without any complication. 
Dihydro-isooxazoline compound 58 is made through the route outlined in scheme 14. Itaconic acid monobutyl ester 55 is chemoselectively converted to allylic alcohol 56 through a mixed anhydride intermediate. The dihydro-isooxazoline core structure 57 can be constructed via a [3+2] cycloaddition approach. Once the core structure is built up, the rest of the chemical transformations are almost the same as those outlined in scheme 9. 
see Scheme 9 for more details about these steps
One enantiomer or diastereomer of a compound of Formula I may display superior activity compared with the others. Thus, the following stereochemistries are considered to be a part of the present invention. 
When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Andrew S. Thompson, et al, Tetr. Lett. 1995, 36, 8937-8940.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.